World Journal of Pharmaceutical Research SJIF Impact Factor 8 - … · 2020-02-29 · Ahmed et al....

Ahmed et al. World Journal of Pharmaceutical Research

www.wjpr.net Vol 9, Issue 3, 2020.

144

REVIEW ON ALZHEIMER DISEASE AND THE IMPLEMENTED

PHARMACEUTICAL APPROACHES

Shadi Fathi Taha, Zhou Jiangping*, Ahmed Alfatih Sirelkhatim Fadul and Omer

Mohamed Omer Ahmed

School of Pharmacy, Department of Pharmaceutics, China Pharmaceutical University, 639

Longmian Avenue, Jiangning District, Nanjing, 211198, P.R. China.

ABSTRACT

Alzheimer's disease was considered a huge health burden for scientists

for many generations and is one of the biggest health problems for

humanity. Since its discovery in 1906 by Alosi Alzheimer, drug

delivery have being the major obstacle. With the presence of a

selective membrane barrier allowing certain molecules to enter and

exit, delivering drugs to the brain was considered a challenge but now,

new cutting edge technologies have been developed allowing scientists

to construct nano sized particles from different materials to bypass the

BBB. Nevertheless, peptides, ligands and coating materials were added

for modification of the particle for better targeting abilities. The

following review focuses on the nanotechnology used for targeting

Alzheimer's disease and the pharmaceutical strategies for drug delivery to the brain as well as

a few collections have been mentioned for the nano sized particle that has been used for drug

delivery, eventually the future perspective will be discussed for better engaging the

Alzheimer's disease.

1-INTRODUCTION

Alzheimer‟s disease (AD), also referred to simply as Alzheimer‟s, is one of the biggest health

problems in current humanity and the most common cause of dementia and considered as a

significant public health problem, generally it starts gradually and worsens over time in older

adults.[1]

Recent investigations concluded that AD is one of the most complex diseases ever

studied. Many factors support such theory based on many challenges that faced those

researchers. To begin with, the brain is an organ like no other in terms of accessibility; a

World Journal of Pharmaceutical Research SJIF Impact Factor 8.084

Volume 9, Issue 3, 144-170. Review Article ISSN 2277– 7105

Article Received on

12 Jan. 2020,

Revised on 02 Feb. 2020,

Accepted on 23 Feb. 2020

DOI: 10.20959/wjpr20203-16945

*Corresponding Author

Zhou Jiangping

School of Pharmacy,

Department of Pharmaceutics,

China Pharmaceutical

University, 639 Longmian

Avenue, Jiangning District,

Nanjing, 211198, P.R. China.



145

complex organ in its structure and function as well as being the most inaccessible organ in the

body, protected by a high selective barrier in which the investigation of any disease is

correspondingly complicated and a difficult task.[2]

AD is characterized by a, language

problems, decline in memory and problem-solving other cognitive skills that affects a

person's ability to perform everyday activities. This decline occurs because nerve cells

(neurons) in parts of the brain involved in cognitive function have been damaged and no

longer function normally.[3,4]

In Alzheimer's disease, neuronal damage eventually affects

parts of the brain that enable a person to carry out basic bodily functions such as walking and

swallowing. People in the final stages of the disease are bed-bound and require around-the-

clock care. In its final stages, Alzheimer‟s disease is ultimately fatal.[5]

An essential extracellular hallmark for AD is the beta-amyloid which is considered

chemically "sticky" and its accumulation will gradually be build up into soluble form and

eventually into plaques. On the other hand neurofibllary tangles are considered as an

essential intracellular hallmark, in which the main transport route for nutrients inside the

neurons are destroyed.[6]

Resulting in formation of tangles that blocks the nutrient

transportation that will cause the death of the neuron. Tau is considered as major protein for

the stability of the intracellular microtubules, its detachment is considered as the major reason

behind the formation of neurofibllary tangles.[7]

Other hallmarks such as Glutamate

excitotoxicity and Acetylcholine deficiency are considered as extracellular hallmarks,

focusing on receptors at the neurons. In which the overactive that happen at the glutamate

receptors causes existoxicity.[8,9]

The over stimulation of the neurons can lead to its death.[10]

As for Acetylcholine which is considered as a crucial neurotransmitter responsible for

transmitting signals between your brain cells and plays a major rule in memory, cognition,

learning and other aspects of higher brain functions.[11,12]

The main obstacle faced by all the researchers for developing an ideal drug delivery method

is the BBB, considered as homeostatic defense mechanism agaisnt pathogens that separate

the major compartments of the central nervous system (CNS) as a primary objective and have

the abilities to prevent entry and actively remove undesirable molecules from the brain.[13]

It's

identified anatomically as microvasculuture of the brain, intercellualer tight junctions of

specially modified capillaries, veins and arterioles.[14,15]

These tight junctions are formed by

the “glued” endothelial cells together with multiple binding proteins (occludins, claudins and

junctional adherin molecules) to form tight junctions (TJs) and adherin junctions (AJs).[16]



146

The barrier uptake essential nutrients, vitamins and hormons while enzymatically degrading

many peptides and neurotransmitter through enzymatic and secratory functions of cells that

comprises its role to BBB communication, homeostasis and nutrition. For cerebral drug

targeting the BBB transport mechanism can be manipulated.[17]

Naturally, the ideal drug

should be small, lipophilic, hydrophobic and compact. In the peripheral circulation,

systematic enzymatic attack and plasma protein opsonization can lead to drug metabloism

before it reaches the brain.[18]

Nanotechnology exerts an increasing impact on the development of more effective tools for

the diagnosis and treatment of human diseases. This applies in particular to central nervous

system (CNS) disorders.[19]

Development of therapeutics for CNS is, in fact, one of the most

challenging areas in drug development, mainly due to the presence of the blood-brain barrier

(BBB) which separates the blood from the cerebral parenchyma thus limiting the brain uptake

of the vast majority of neurotherapeutic agents.[20]

It‟s crucial to development various

nanocarriers that possess both blood brain barrier permeability and ability of targeting one or

multiple AD hallmarks simultaneously with sufficient bio-availability and biodegradability

for optimal delivery, is of great importance for the intervention of AD.[21,22]

The following review article discuss the drug delivery method that have been developed to

deliver various therapeutics targeting AD hallmarks, and the nature of the cargo including its

synthesis method and the materials used for that. Nevertheless, the functionalization materials

which can be used to modify the drug cargo and its ability to bind at the site of action as well

as the different methods and materials used to enhance the BBB permeability. This review

also discusses the future perspective in which the recent limitations facing many research

works can be better engaged, for an ultimate drug delivery method.



147

Figure 1.

2-Nano-technology

Advanced technology is needed for better approach and understanding of the disease to

overcome the problems and limitations caused by previous drug delivery methods.[23]

The

most recent technology for such purpose is the nano-sized particles, with small size and high

drug loading ability of various therapeutics, as well as its ability to be modified with different

materials which can be used for its protection and highly specific for site targeting, nano-

sized particles are considered as cutting edge technology for its ability to delivery

therapeutics.[24,25]

Such technology has offered the scientist with many advantages, such as its

ability to maintain drug levels in a desirable range for therapeutic purpose, as well as it can



148

increase the permeability across the BBB and extending the half-life as well as the solubility

and stability.[26]

Nevertheless, nanotechnology can be designed to serve the disease as

required, for example the system can be designed to release the drug in a controlled manner

or trigged manner depending on the desired release way. For designing a nano-sized particle

2 aspects should be taken in consideration, which are the carrier (nano-sized particle), and the

other is a therapeutic agent (cargo).[27]

Depending on the specific properties of either

component of the system, the drug is adsorbed or conjugated to the surface of the

nanoparticle, or encapsulated and protected inside the core.

2.1-Pharmaceutical Strategies for delivery of AD drugs

Suitable drug carriers that can transport therapeutics across BBB for the treatment of

Alzheimer‟s disease can be enhanced using nanoparticles.[28]

Other approaches also involve

the use of different biochemicals to modify the drug nano-carriers or the therapeutic material

and methods of local delivery. Recent research shows the use of focused ultrasound and

bilized microbubbles that can enhance transport or bypass the BBB by causing disruptions in

the tight junction of the brain endothelial.[29]

The improved delivery of drugs across the BBB

has been shown over the use of many different systems and established using a wide

collection of methodologies, in vitro and in vivo.[30]

All of these investigations seem

promising; nevertheless the absence of consistent approaches has made challenging to track

down any one best technique for a given disorder.[28,31]

As many of the recent clinical trials

fails because of the poor investigation concerning the BBB penetration, the BBB remain as

the main obstacle for this investigations.[32]

As the BBB interference or the administration of

the drug straight into the brain is not a route due to toxic effects and low diffusion of the

therapeutic molecule in the brain parenchyma. A promising approach for drug systemic

delivery to the central nervous system is the use of nano-sized carriers.[29,33]

2.2-The use of Nanotechnology for AD therapy

Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid

lipid carriers, carbon nanotubes, metal based carriers and many others have been adapted to

develop successful therapeutics with sustained release and improved efficacy.[34]

The use of

Nano-carriers is a fast developing field for medical application, nanoparticles or

nanostructures are highly expected for the ability to delivery drug through the BBB.[35,36]

They are characterised as colloidal structures comprising of natural or synthetic polymers

ranging in size from 1 to 1000nm.[37]

The application of this nanotechnology in drug delivery



149

systems has developed the kinetic profile of drugs in biological systems as well as its

bioavailability.[21]

The development of nanotechnology aid in directing drugs to specific

molecular targets and safely delivers drugs to specific sites of action.[37]

The sustained release

of nano-drug delivery systems enhances the controlled release profile of loaded drugs,

thereby minimizing the dosage-regimen. Thus, the overall effectiveness of drug candidates

can be enhanced by adapting nano-drug delivery.[38]

At present NPs are found to play a

significant advantage over the other methods of available drug delivery systems to deliver the

drug across the BBB.[39,40]

Due to their size and functionalization, nanoparticles are able to

penetrate and facilitate the drug delivery through the barrier, including number of

mechanisms and strategies found to be involved in this process, which are based on the type

of nano-materials used and its combination with therapeutic agents, such materials include

polymeric nanoparticles non-viral vectors of nano-sizes for CNS gene therapy and liposomes

etc.[21,41,42]

In which the therapeutic molecule (Ex:protein or peptide) is incorporated

internally either encased by the polymer matrix or distributed throughout, and can have

external additions such as PEG and ligands to increase stability and specificity of targeting,

respectively.[41]

They are mainly produced by emulsion/solvent evaporation or precipitation

solvent diffusion from a variety of polymers such as dextran, starch etc. As an advanced

technology, nanoparticles are expected to reduce the need for invasive procedures for

delivery of therapeutics to the CNS as various number of drug delivery systems have been

used such as liposomes, nano-gels and nano-biocapsules microspheres and nanoparticles to

improve the bioavailability of the drug in the brain, but microchips and biodegradable

polymeric nano-particulate careers are found to be more effective therapeutically in treating

brain tumor.[43]

Many limitations minimize the effect for nanotechnology such as the

presence of the blood–brain barrier (BBB), which highly regulates drug permeation, lack of

unique target biomarkers for the diseased cells and the presence of highly selective barriers,

and cell types which strongly influence the interaction with nanoparticles by the presence of

lipid composition, surface receptor and interaction of nanoparticles with biological

components after administration and physical factors that also contribute to the overall

limitations and the concentration of the nanoparticles in the brain blood vessel, blood

circulation, accumulation in non-target organs and elimination.[44,45]

Recently, a wide range

of nano-carriers, with different modifications such as polymers, emulsions, lipo-carriers, solid

lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop

successful therapeutics with sustained release and improved efficacy by facing all the

limitations caused by the brain.[46]



150

Figure 3: The following figure shows how nanotechnology is applied for Alzheimer

disease treatment.

2.3-BBB and Brain receptors

BBB or Blood Brain Barrier can be considered as nutrient provider for the brain as it supply

it with the necessary alimentary for the brain to operates in a healthy manner. However, it

restricts the movement of ions and fluid to ensure an optimal environment for brain function

as well as prevents the introduction of harmful substances to the brain. To a certain extend

that can beneficial, yet BBB was always considered as an immense obstacle for many

systemic delivery of neurotherapeutics.[47]

After decades sicentist were able to find a window

of opportunity for certain molecules with specific size, mainly the lipid-soluble with size 400-

600 Da or less, making it the difficult accessible organ by numerous molecules. On the other

hand, the BBB efflux transport systems was another milestone that researchers had to

encounter, in which the drugs that meet the criteria are exported from the brain. Nonetheless,

other organs have tight junctions that helps nutrients to reach them by slipping between blood

vessel endothelial cells, but when it comes to brain the its entirely different, tight junctions

present at the brain are consist from protein structures that button up the membranes of

neighboring endothelial cells near their blood-facing, or luminal, ends. Thus, the brain

vasculature restrict the flow of molecules from the blood to the CNS.[49]

Receptors that

promote the transfer of various macro-molecule are present on the BBB, which is accessible

for drug transport (~20 m2) that is more than adequate for treating the whole brain volume,

the barrier properties of the BBB continue to limit brain drug delivery via the bloodstream.[50]

Other necessary nutrients that is needed for the brain to function such as proteins, amino

acids and water-soluble compound such as ions and vitamins possess specific transport

systems enclosed in the plasma membranes of the BBB to permit brain entry. There are two

primary classes of transport systems function at the BBB. The first, carrier-mediated transport,

relies on molecular carriers present at both the apical (blood) and basolateral (brain)



151

membranes of the BBB. These carriers tend to be highly stereospecific and function in the

selective transport of small molecules such as ions, energy sources and amino acids. Using

carrier-mediated transport systems for noninvasive drug delivery by conjugating therapeutics

to the natural substratese. One factor to take into consideration is that since carrier-mediated

transport systems are typically small, stereospecific pores, they are not particularly amenable

to the transport of large-molecule therapeutics. While the other is the Receptor-mediated

transport mechanisms are also present at the BBB, and these involve the vesicular trafficking

system of the brain endothelium). Brain influx of nutrients such as iron, insulin, and leptin

occurs by a transcellular, receptor-mediated transport mechanism known as transcytosis.

Table 1.

Receptor-Mediated transport (RMT) Carrier-mediated transport (CMT)

Transferrin receptor (TFR) Glucose transporter 1 (GLUT1)

Insulin receptor (IR) Organic anion transporting polypeptide (OATP)

Lipoprotein receptor (LPR) Large neutral amino acid transporter (LAT)

Diphtheria Toxin receptor (DPTR)

Receptors expressed on blood brain barrier are located on both luminal side (blood) and

abluminal, in which the following receptors possess the ability to regulate trafficking of

different molecules, including essential nutrient and drug molecules.

Figure 2: Nano-particles are modified with peptide ligands that bind with various

receptors at the brain endothelial promoting transcytosis. The targeting to endocytic



152

cell-surface receptors present on brain endothelial cells allows for binding and

transport across the cell trough vesicular transcytosis. Receptor-mediated transport

receptors include TfR, LRP1, IR, LDLR, ObR and nAChR.

3-NANOPARTICLE USED FOR AD MEDICAL APPLICATION

3.1-HDL-like nanoparticles

Known as the good cholesterol, High density lipoproteins are considered as natural nano-

carriers with different shapes as well as protein and lipid composition. They are well

recognized for their biological role and are highly suitable as a nano-platform for medical

diagnostics and therapeutics. In human, lipoprotein metabolism consist of two interrelated

pathway, in the first pathway, the apolipoprotein B which delivery lipids consist mainly of

cholesterol and triglycerides from intestine and liver to other tissues.[51,52]

Another pathway is

the use of HDL to remove the excess cholesterol from the blood vessels and transport it to the

liver in a process known as revers cholesterol transport.[53]

When compared with other

lipoproteins, HDL is quite dense and considered as small lipoproteins due to the availabili ty

of apolipoprotein. Now day‟s scientist has developed the synthetic form of HDL, with many

advantages and modification to its structure and constituent. Recent investigation for the

different uses of synthetic HDL has shown its effectiveness in atherosclerotic arteries, by

removing the excess cholesterol after that its deliver it to the liver for elimination.[54,55]

Yet

many limitations face the synthetic form of HDL, such as the short half-life as well as the

narrow therapeutic index, and here where comes the use of different modification materials

which can be attached to the surface of the sHDL or to the component used for its

synthesis.[56]

Its natural role is the reverse cholesterol transport, and that‟s how the excess

cholesterol is removed from the periphery and delivered to the liver for excretion. Beside that

natural HDL have other vasoprotective roles including its reduce the endothelium

inflammation, regulate the vascular tone by increasing nitric oxide and induction of

endothelium repair.[57]

HDL structure

Many strategies have been developed to increase the level of HDL and improving its role for

targeted therapy. For example the synthetic HDL has been used to target the acute coronary

syndrome (ACS), in which it was used to successfully reduce the platelet aggregation.[58]

The

synthetic form of HDL have been constantly developed to resemble the natural HDL,

specially the components used for the establishing the sHDL surface. The natural HDL



153

synthesis begins in the liver and small intestine where ApoA-1 the crucial protein which

make 70% of the protein composition of the HDL, which its main source, Thus forming the

first structure of HDL which is the lipid free.[59, 60]

Table 2: Examples of the structural diversity of HDL-like NPs for drug delivery.

Structural feature Examples

Particle core form Cholesterol esters

Inorganic scaffolds (Au)

Shape Discoidal

Spherical

Protein associated with

particle

Full-length apoA-I

ApoA-I-mimetic peptide

ApoE

Phospholipids

Phosphatidylcholine

1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)

1,2-dimyris-toyl-sn-glycero-3-phosphocholine (DMPC)

1,2-dioleoyl-sn-glycero-3-((N(5-amino-1-

carboxypentyl)iminodiacetic acid) succinyl)(- nickel salt) (NiLipid)

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-

[folate(polyethylene glycol)-2000] (DSPE-PEG2000-folate) (PF)

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-

pyridyldithio)propionate] (PDP PE)

[Dipalmitoylphosphatidylcholine (DPPC)

Pyropheo-phorbide conjugated to the glycerol backbone of

lysophospholipids

Lipid layer surrounding

the particle

Monolayer

Bilayer

Mechanism of drug

loading

Covalent attachment

Encapsulation

Integration in lipid layer

Lipid-free apoA-I has garnered significant interest of late because the absence of lipid

appears to be a requirement for the interaction of apoA-I with the ABCA1 transporter, a key

reaction for the maintenance of plasma HDL levels. As for the ApoA-1 consist of both polar

ad non-polar surface, it gives the lipid free ApoA-1 ability to possess negative and positive

charges and is highly solvent exposed. Lipids play a key role to determine its shape, giving

the lipid free ApoA-1a structure of amphipathic alpha-helices.[61,62]

The second structure is the lipid poor –HDL, which have the structure of a disc shape, consist

of two rings of ApoA-1 one at the top and the other is at the bottom wrapping with its main

component the ApoA-1 with the ability to solubilize the phospholipids around phospholipids

bilayer in a double belt model.[63]

Which are generated by exposure of lipid-free apoA-I to the

cholesterol/phospholipid transfer activity ABCA1.



154

The lipid rich HDL particle is the dominant form of HDL in the human plasma. That has a

spherical structure in which the amphipathic helices of ApoA-1 situated on the surface of the

molecule and contains a neutral lipid core composed of cholesteryl ester and triglyceride.

Reconstituted HDL nanoparticle has the ability to carry different types of drugs.

Figure 4.

3.2-Polymeric-Nano-carriers

Natural and plant-based polymers could be used for control release of drugs and also helps in

targeting drug to the site of action, Polymeric NPs are solid colloidal carriers composed of

synthetic, semi-synthetic or natural polymers with size ranging from 10 to 1000nm.[64]

In

which they are categorized as either nano-spheres or nano-capsules. In nano-spheres, drug is

isolated in polymeric matrix however nano-capsules are reservoir system in which drug is

limited within a polymeric shell.[65]

Both polymeric nano-spheres and nano-capsules have

been discovered for the delivery of peptide and protein therapeutics. Many aspects affect the

properties of polymeric nanoparticles such as the nature of the polymer synthetic or natural as

well as the preparation process involved. Polymeric nanoparticles considered as an innovative

strategy for enhanced delivery method for non-invasive drug delivery routes such as nasal,

pulmonary transdermal, and oral.[66]

Therapeutic molecules can be adsorbed, encapsulated or

chemically linked to the surface of polymeric NPs. Several techniques can be used for the

incorporation of proteins and peptide in polymeric NPs.[67]

Natural polymers are usually more

likely to be sensitive to processing conditions. Hence, NPs with natural polymers are

generated using mild techniques including ionic gelation, coacervation and polyelectrolyte.

Recently polymeric NPs helps to with the problems related with synthetic and metallic

polymer based NPs.[68]

To overcome for the preparation of NPs polysaccharides of natural

origin have been used as polymers to overcome the problems associated with metallic and



155

synthetic polymer-based NPs.[69]

To avoid the use of toxic chemicals, high-cost and to

prevent toxic effect of by-products of synthetic polymers, plant-based polymers that are

abundantly available in nature may be evaluated for their composition, structure and

toxicity.[70]

Figure 5.

In an investigation conducted by Liangfang zhang et al, who designed a self-assembled lipid-

polymer hybrid nanoparticle as a potent drug delivery for its ability to combines both the

merits of the polymeric NPs and liposomes.[71]

Liangfang zhang et al, has used the nano-

precipitation or double emulsion methods which are both considered simple to carry out and

scalable methods for nano-system preparation. The system was consisted of a hydrophobic

polymeric core and a hydrophilic polymeric shell and a lipid monolayer at the interface of the

core and the shell. His nano-system was self-assembled via the PLGA (poly (D,L-lactic-co-

glycolic acid) terminated with ester linkage as a model of hydrophobic polymer to form the

polymeric core of the nano-system.[72]

The polyethylene glycol (PEG) which can be used for

coating the NP and prolong its circulation. It has been demonstrated that the hybrid NP has

tunable size and surface charge, high drug loading yield, sustained drug release profile,

favorable stability in serum, good cellular targeting ability and its simple synthesis process

may be amenable to further scale-up if desired. All these positive attributes make the lipid-

polymer hybrid NPs a promising drug delivery vehicle for further in vivo evaluation.[73]

In

another study, Zhang et al designed an advanced dual-functional NP drug delivery system

which is consist of PEGylated poly(lactic acid) polymer containing two targeting peptides,

TGN and QSH, conjugated to the surfaces of the NPs. TGN specifically targets ligands at the

BBB, while QSH has good affinity for Aβ1–42, which is the main component of amyloid

plaques.[74]

In this study, the optimal maleimide/peptide molar ratio was 3 for both TGN and

QSH on the surface of the NPs. These NPs were delivered to amyloid plaques with enhanced

and precisely targeted delivery in the brains of AD model mice.



156

3.3-Liposomes

Liposomes were discovered in the 1960s, since then they were under constant investigation,

liposomes were valued for their technological and biological merits, and considered as very

reliable and one of the most successful drug-carrier system up to date.[75]

It consists of

vesicular self-assembling colloidal structures composed of one (unilamellar) or more

(multilamellar) lipid bilayers surrounding a core aqueous compartment. The aqueous core

provides an environment in which hydrophilic drugs can be encapsulated, while lipophilic

drugs can be incorporated into the lipid bilayer. Its first formulation was composed only of

natural lipids, now day‟s man things can be added to it such as natural and or synthetic lipids

and surfactants. Their structure is nearly spherical with size range from few nanometers to

several micrometers, but as for the desirable size for therapeutic purpose it ranges from 50 to

450 nm. Liposomes have similar morphology of cell membrane giving it the ability to

incorporate various therapeutic and functionalization material.[76]

In a study conducted by

KARTHIK ARUMUGAM et al, in which rivastigmine a class of acetyl-cholinesterase

inhibitors for mild to moderate alzheimer patients, and liposomes as the drug vehicle by

intranasal route. For the liposome formulation, lipid bilayer method hydration was used, by

using cholesterol and soya lecithin as lipid components.[77,78]

A rat model was used to check

the amount of free drug administrated orally and intranasal as well as intranasal liposome

rivastigmine. The samples were divided into 3 groups for the vivo study, all 3 groups

received same amount of rivastigmine in which the 1st group was the free drug administrated

orally, group 2nd

was also a free drug but administrated intranasal and the 3rd

sample was

liposomes administrated through intranasal route.[79-81]

The AUCs of these groups were

compared, the intranasal liposome group had five-fold higher AUC (36.13 ± 1.87 mg min

mL–1) when compared to orally administered free drug (6.58 ± 0.26 mg min mL–1) and an

almost three-fold higher value compared free drug administrated intransally (12.99 ± 0.87 mg

min mL–1). This concluded that intranasal liposome rivastigmine had longer half-life than

the free drug intranasal and the oral administration.

In a study recently conducted from Mourtas et al, focusing on using liposome for targeting A-

beta amyloids using azido-decorated liposomes functionalization with an alkyne-derivatized

ligand by 1,3-dipolar Huisgen cycloaddition reaction (Also known as click chemistry

reaction).[82]

The research group found out by SPR experiments that the liposomes decorated

with the planar curcumin had the highest affinity constant (in the 1–5 nM range) reported

thus far for Aβ fibrils, whereas nonplanar curcumin-decorated liposomes did not show any

https://www.sciencedirect.com/topics/engineering/functionalization



157

binding.[83,84]

As for the polymer NPs, these systems could pave the way for the development

of colloidal systems able to capture Aβ as one of the most occurring hallmarks for AD and to

reduce its inherent toxicity.[85,86]

3.4-Solid lipid nano-carriers

The SLN are spherical in structure with size range from 10 to 1000m in diameter. In the late

19th

century solid particles were established and had advantages over the liposomes and in

terms of protection incorporated active compounds against chemical degradation and more

flexibility in modulating release of the compound.[87]

By gaining such conclusion about the

solid nanoparticle, in the 1990s emulsions and liposomes were combined by the development

of the „solid lipid nanoparticles‟ (SLN). The SLN released by simply exchanging the liquid

lipid (oil) emulsions by a solid lipid, which means lipids solid at room temperature but also at

body temperature.[88]

SLN is been rapidly developed for drug delivery and research work, due

to their abilities and numerous nanocarriers which were based on solid lipid such as solid

lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugates.

In a study conducted by Bondi et al. a developed ferulic acid-loaded SLN was established by

using the microemulsion technique for AD therapy.[89]

In the study, two SLN was tested for

their effectiveness, the ferulic acid-loaded and the unloaded SLN. Both ferulic acid-loaded

and the unloaded SLN was synthesized by using the oil in water micro-emulsion technique.

The samples that were loaded with ferulic acid –SLN showed a fully drug release within 10

hours at a neutral pH of 7.4.On the other hand the unloaded SLN were able to penetrate the

cell membrane with no cytotoxic effect on cell proliferation.[90]

Based on his research, Bondi

et al. proved that the loaded FA- SLN possessed higher protective activity in comparison with

the unloaded SLN against oxidative stress induced in neurons concluding the SLN are

excellent carries for transporting FA into the cells, which on the other hand can be considered

as a potential drug delivery system for Alzheimer disease.[91]

The investigation and different methods was carried out for inhibiting the formation of

β‐amyloid. Girish Modi et le. Worked on the use of nanogels as an advanced nanotechnology

for inhibiting the formation of β‐amyloid, his nanogel was modified with polysaccharide

pullulan backbones with hydrophobic cholesterol moieties (cholesterol‐bearing pullulan,

CHP) as artificial chaperones to inhibit the formation of β‐amyloid (1–42) fibrils with marked

amyloidgenic activity and cytotoxicity.[92]

The nanogel was biocompatible and 20–30 nm in



158

diameter as well as its ability to prevent aggregation of proteins associated and inhibit

amyloid fibers from forming.[93]

Cholesterol‐bearing pullulan, CHP-nanogel were able to

incorporate up to 6-8 of β‐amyloid (1–42) molecules per particle and prompt a change in the

conformation of β‐amyloid from a random coil to an alpha‐helix‐ or β‐sheet‐rich structure.

The nanogel showed high level of stability in 24hour period under 37 degrees, under such

conditions the CHP-nanogel was able to inhibit the aggregation of β‐amyloid. Nevertheless,

Girish Modi et le order to release monomeric β‐amyloid molecules, the nano-gel had to be

dissociated by the addition of methyl‐β‐cyclodextrin.

In a study c+onducted by Jorge Palop et.al, a PhD candidate at Gladstone Institutes, working

on a possible cell therapy for AD treatment, that the transplanting of genetically altered

interneurons for improving cognitive function can possibly be effective against AD. The

main theory of this method focuses on the damaging specific neurons which can alter brain

wave and rhythms, and inhibiting interneurons that are especially important for managing

brain rhythms. Interneurons control complex networks between neurons, by permitting

signals to be sent to one another in a harmonized manner.[94,95]

An imbalance between 2

type‟s neurons can create tension leading to multiple neurological and psychiatric disorders

including autism, AD etc. Palop worked previously on inhibiting interneurons in mouse

models with AD, resulting in poor effectiveness due to the disturbance of rhythms that

organize the excitatory, causing an imbalance in the brain network and cells fail to function

harmoniously, leading to poor memory formation and epileptic activity.[96]

The researchers at

Gladstone Institutes noticed that the functions of interneurons was in enhanced as well as it

activity been genetically improved when adding a protein called Nav1.1.[95]

Nevertheless,

such discovery was concluded by overcoming the toxicity at the disease environment and

restoring brain function.[97]

3.5-Virus like particles (VLPs)

On molecular level virus like particle resembles natural virus but since they lack viral

genomes, making them absolutely noninfectious, nonetheless VLPs they can be

naturally come about or synthesized through the individual expression of viral structural

proteins. Many viral structural proteins have an intrinsic ability to self-assemble into virus-

like particles (VLPs).[98]

Virus particle consists of various parts including the genetic material

(DNA or RNA), a protein coat that protects these genes, and in some cases an envelope of

lipids that surrounds the protein coat when they are outside a cell. The size of viruses ranges



159

from a few tens to a few hundreds of nm, which is equal to 1/100 to 1/1000 of the cell (a few

to a few tens of μm in size) of any other common living organism. V LPs make excellent

vaccines against the virus from which they were derived.[99,100]

VLP-based vaccines to

prevent infection by two viruses, Hepatitis B Virus and Human Papillomavirus, have been

approved for human use. Both of these vaccines safely and consistently induce high titer,

durable antibody responses in humans.[101]

In a study conducted by Bryce chackerian et.al,

using VLP-based vaccines for immunoprophylaxis against an amount of other human virus

infections are in clinical and preclinical development. VLPs make effective vaccines because

their particulate nature and multivalent structure provoke strong immune responses.[99,102]

VLP-based platforms have certain advantages for the develop-ment of vaccines for AD. They

are highly immunogenic and can even overcome the effects of immune tolerance that may

exist in AD patients. Their modular nature allows for the display of different A-beta derived

peptides. They can serve as a source of linked T helper epitopes, meaning that T-cell

responses need not be directed against A-beta. Indeed, VLP-based immunogens for AD have

been tested in animal models and can induce high titer anti-body responses against A-beta

without concomitant T-cell responses and can reduce A-beta-related pathology. The current

CAD106 clinical trial will establish whether a VLP-based vaccine against A-beta can

mitigate disease in humans.

4-NANOPARTICLE FUNCTIONALIZATION

4.1-Nanoparticle Functionalization

Different nano-carriers can be loaded with various functionalization materials for longer

bioavailability, protection from interaction with blood protein serum, very specific for

targeting receptors located at the BBB. Nevertheless, recently many functionalization

materials are been constantly developed for targeting different receptors on the BBB with

high affinity with different possible routes based on receptors and absorptive transocytosis.

Materials used for the functionalization can be protein, peptide and other coating materials,

attached to the nano-carriers with different methods based on their chemical and physical

properties. The four most abundant receptors located on the BBB are Tfr, insulin and leptin

yet targeting these receptors have been an overwhelming task for many years.[53]

As the

ligands used for targeting the receptors can vary in size and chemical composition causing

difficulty for their attachment with the carrier and the possibility of interactions with blood

protein serum before reaching their site of action. Proteins were the main materials used for

functionalization, by time their production was expensive and high immunogenicity was a



160

major issue. Eventually researchers turned their eyes to much smaller molecules, with huge

amount of study focusing on their method of purification and production. Peptides were

considered a very attractive candidate, their conjugation with the nano-carrier resulted in

minimizing the undesirable side effects and achieves the therapeutic effect with a lower

dose.[103]

Both linear and cyclic peptides have been explored as trafficking moiety due to ease

of synthesis, structural simplicity, and low probability of undesirable immunogenicity. These

molecules combine the low cost of small drugs with the high specificity of biologics. As

peptides are easy to modify, their attachment with the receptor should meet with certain

requirements to ensure accurate binding with the targeted site. At first the peptide should bind

with the receptor expressed on the targeted cell, and no other cells expressing the same

receptor, as well as its stability during the systematic circulation to ensure effective

concentration. Other crucial factors that plays a key role in designing an optimal drug

delivery system is the drug release, which is the process by which the drug is released by

diffusion or the release of drug by dissolution of the nano-carrier matrix is known as drug

release.[104]

It‟s a crucial step in the overall drug delivery system as it can help to determine

the drug stability, formulation development and therapeutic site. The effectiveness of the drug

is related to the drug component as well as the solubility and the diffusion. After the

administration of the drug through a nano-carrier, other parameters are considered to check

the effectiveness such as the particle size and release process.[105]

For faster drug release the

size of the particle is a key factor, in which the smaller particle size the larger the area to

volume ratio, resulting in the drug being close to the surface of the particle in which the drug

is released faster. An overall optimal drug release will depends on many factors, at first the

design of the nano-carrier, and fully understanding the process by which the nano-carrier is

affected by the inner environment of the systemic circulation eg:(pH and thermo-sensitivity),

with full knowledge of the physiological factors as well as the time of release and site of

therapeutic.

4.2-Safety issues concerning the use of nanotechnology for Alzheimer treatment

The evolvement of nanotechnology and its applications for Alzheimer disease treatment have

promoted serious issues in relation to NP-mediated toxicity and adverse reactions.[106]

Making it a huge concern for IV injected Alzheimer‟s nanoparticle loaded medicines,

regardless to their uses whether for reaching the brain for diagnostic imaging or therapeutic

purposes.[107]

In particular, nanoparticles size, shape, and surface characteristics can modulate

pharmacokinetics and biodistribution. Investigation in this area of research is still scant and

https://www.sciencedirect.com/topics/medicine-and-dentistry/nanomedicine

https://www.sciencedirect.com/topics/medicine-and-dentistry/diagnostic-imaging

https://www.sciencedirect.com/topics/engineering/therapeutic-purpose

https://www.sciencedirect.com/topics/engineering/therapeutic-purpose

https://www.sciencedirect.com/topics/materials-science/surface-characterization

https://www.sciencedirect.com/topics/medicine-and-dentistry/pharmacokinetics



161

particularly in relation to the brain. However, from the therapeutic perspective the benefit-to-

risk ratio is a crucial point that researchers should pay much attention to, depending on the

nanoparticles dose and on the frequency of dosing.

5-CONCLUSION

Nanotechnology is able to provide potent agents to modify the course of specific pathological

mechanisms involved in AD. Even though, translation of these strategies to actual

modification of Alzheimer‟s disease course in human subjects lies largely not only on

biocompatibility of these agents, all disease modifying strategies designed to slow or halt the

Alzheimer‟s disease molecular pathogenesis have failed by phase-3 clinical trials. The

chances of finding a cure for AD in the future are low, there is also no considerable research

progress explaining the underlying mechanisms of AD. Establishing and validating relevant

animal models used in preclinical studies, and methodologies used in drug design and

discovery has no promising research future either. While toxic side effects remain the major

concern regarding different nanoparticles. Methodological breakthrough in targeted particles

is shown by their biochemical characteristics. The structural barrier (BBB) imposes

boundaries and sets limits to the delivery of therapeutic drugs to the brain which makes

treating patients suffering from tumors, virus generated neuronal infections, and

neurodegenerative diseases a very demanding task. Therefore, several diverse techniques

have been developed and put to use for both direct and indirect drugs delivery to the brain in

order to achieve proper drug delivery to patients. In several case studies direct injections or

convection-enhanced drug delivery or cerebrospinal fluid or intranasal delivery verified their

unreliability by being problematic to the patient or fails. Nonetheless, biodegradable

biomaterials should be used to minimize toxic effects in the brain in order to have a lower

risk of nanoparticle generated cytotoxicity and invasiveness. Furthermore, Biomaterials for

making nanoparticle should be biocompatible and should have a very short half-life.

Therefore, biodegradable polymers like polylactic acid, polycaprolactone, poly (lactic-co-

glycolic acid), the poly (fumaric-co-sebacic) anhydride chitosan, and modified chitosan, as

well as solid lipids, should be used in the preparation of the nanoparticles. Other drug nano-

carrier such as the reconstituted HDL services as an excellent therapeutics delivering vehicle

and it unique size making the penetration of the BBB more likely with the right peptide

ligands. According on that, A solid argument could be made stating that the field has a good

understanding of at least the generalities of apoA-I organization in its lipid-free form and in

simple discoi-dal particles. Although, more research needs to be done in order to understand



162

the importance of the more dynamic sequences within these structural frameworks for better

application for Alzheimer disease. Moreover, active drug molecules can be coupled to a

desired protein or peptide that increases its circulating life, solubility, stability and

antigenicity. To wrap it up. Moreover, active drug molecules can be coupled to a desired

protein or peptide that increases its circulating life, solubility, stability and antigenicity. To

wrap it up, plenty of studies have focused on applications of various drug delivery system and

their modifications, however, more research need to be conducted to better understand the

materials used for constructing the drug carrier as well as the conjugates peptides.

Researchers should have better understanding of the mechanisms underlying the beneficial

biological properties of materials used for constructing the drug carrier as well as the

conjugates peptides since they offer incredible opportunities which will in return promote

more rational drug design.

6-ABBREVIATIONS

AD Alzheimer disease

BBB Blood Brain Barrier

TJs Tight junctions

AJs Adherin junctions

HDL High density lipoprotein

Aβ Amyloid beta

RMT Receptor-mediated transcytosis

SLN Solid lipid nanoparticle

NP Nanoparticle

PEG Polyethylene glycolated.

PLGA Poly(lactic-co-glycolic acid)

IV Intravenous

FA Ferulic acid

CHP Cholesterol‐bearing pullulan

ACS Acute coronary syndrome

TfR Transferrin receptor

CNS Central nervous system

PAMAM Poly(amidoamine)

VLPs Virus like particles

SLN Solid lipid nano-particles



163

DNA Deoxyribonucleic acid

RNA Ribonucleic acid

8-REFERENCES

1. Bayati, A. and T. Berman, Localized vs. Systematic Neurodegeneration: A Paradigm Shift

in Understanding Neurodegenerative Diseases. Front Syst Neurosci, 2017; 11: 62.

2. Gu, X., H. Chen, and X. Gao, Nanotherapeutic strategies for the treatment of Alzheimer's

disease. Ther Deliv, 2015; 6(2): 177-95.

3. Campos-Pires, R., et al., Xenon improves long-term cognitive function, reduces neuronal

loss and chronic neuroinflammation, and improves survival after traumatic brain injury

in mice. Br J Anaesth, 2019; 123(1): 60-73.

4. Millan-Calenti, J.C., et al., Optimal nonpharmacological management of agitation in

Alzheimer's disease: challenges and solutions. Clin Interv Aging, 2016; 11: 175-84.

5. Villemagne, V.L., et al., Amyloid beta deposition, neurodegeneration, and cognitive

decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol, 2013;

12(4): 357-67.

6. Medina, M. and J. Avila, The role of extracellular Tau in the spreading of neurofibrillary

pathology. Front Cell Neurosci, 2014; 8: 113.

7. Sergeant, N., et al., Biochemistry of Tau in Alzheimer's disease and related neurological

disorders. Expert Rev Proteomics, 2008; 5(2): 207-24.

8. Kole, A.J., R.P. Annis, and M. Deshmukh, Mature neurons: equipped for survival. Cell

Death Dis., 2013; 4: e689.

9. Buss, R.R., W. Sun, and R.W. Oppenheim, Adaptive roles of programmed cell death

during nervous system development. Annu Rev Neurosci, 2006; 29: 1-35.

10. Buss, R.R. and R.W. Oppenheim, Role of programmed cell death in normal neuronal

development and function. Anat Sci Int, 2004; 79(4): 191-7.

11. Cherry, K.M., E.J. Lenze, and C.E. Lang, Combining d-cycloserine with motor training

does not result in improved general motor learning in neurologically intact people or in

people with stroke. J Neurophysiol, 2014; 111(12): 2516-24.

12. Tyng, C.M., et al., The Influences of Emotion on Learning and Memory. Frontiers in

Psychology, 2017; 8(1454).

13. Zhou, Y., et al., Crossing the blood-brain barrier with nanoparticles. J Control Release,

2018; 270: 290-303.



164

14. Nafee, N. and N. Gouda, Nucleic Acids-based Nanotherapeutics Crossing the Blood

Brain Barrier. Curr Gene Ther., 2017; 17(2): 154-169.

15. Hindle, S.J. and R.J. Bainton, Barrier mechanisms in the Drosophila blood-brain barrier.

Frontiers in Neuroscience, 2014; 8(414).

16. Cotran, R.S. and G. Majno. Studies on the Intercellular Junctions of Mesothelium and

Endothelium. 1967. Vienna: Springer Vienna.

17. Salama, N.N., N.D. Eddington, and A. Fasano, Tight Junction Modulation and Its

Relationship to Drug Delivery, in Tight Junctions. 2006, Springer US: Boston, MA.,

206-219.

18. Tolar, M., S. Abushakra, and M. Sabbagh, The path forward in Alzheimer's disease

therapeutics: Reevaluating the amyloid cascade hypothesis. Alzheimers Dement, 2019.

19. Wong, H.L., X.Y. Wu, and R. Bendayan, Nanotechnological advances for the delivery of

CNS therapeutics. Adv Drug Deliv Rev, 2012; 64(7): 686-700.

20. Micheli, M.R., et al., Lipid-based nanocarriers for CNS-targeted drug delivery. Recent

Pat CNS Drug Discov, 2012; 7(1): 71-86.

21. Saeedi, M., et al., Applications of nanotechnology in drug delivery to the central nervous

system. Biomed Pharmacother, 2019; 111: 666-675.

22. Gao, H., Z. Pang, and X. Jiang, Targeted delivery of nano-therapeutics for major

disorders of the central nervous system. Pharm Res, 2013; 30(10): 2485-98.

23. Singh, A.P., et al., Targeted therapy in chronic diseases using nanomaterial-based drug

delivery vehicles. Signal Transduct Target Ther, 2019; 4: 33.

24. Jain, R.K., Barriers to drug delivery in solid tumors. Sci Am, 1994; 271(1): 58-65.

25. Bamrungsap, S., et al., Nanotechnology in therapeutics: a focus on nanoparticles as a

drug delivery system. Nanomedicine (Lond), 2012; 7(8): 1253-71.

26. Srikanth, M. and J.A. Kessler, Nanotechnology-novel therapeutics for CNS disorders. Nat

Rev Neurol, 2012; 8(6): 307-18.

27. Balducci, C. and G. Forloni, Novel targets in Alzheimer's disease: A special focus on

microglia. Pharmacol Res., 2018; 130: 402-413.

28. Bhaskar, S., et al., Multifunctional Nanocarriers for diagnostics, drug delivery and

targeted treatment across blood-brain barrier: perspectives on tracking and

neuroimaging. Part Fibre Toxicol, 2010; 7: 3.

29. Kasinathan, N., et al., Strategies for drug delivery to the central nervous system by

systemic route. Drug Deliv, 2015; 22(3): 243-57.



165

30. Martin-Rapun, R., et al., Targeted Nanoparticles for the Treatment of Alzheimer's

Disease. Curr Pharm Des., 2017; 23(13): 1927-1952.

31. Sadowska-Bartosz, I. and G. Bartosz, Redox nanoparticles: synthesis, properties and

perspectives of use for treatment of neurodegenerative diseases. J Nanobiotechnology,

2018; 16(1): 87.

32. Song, K.H., B.K. Harvey, and M.A. Borden, State-of-the-art of microbubble-assisted

blood-brain barrier disruption. Theranostics, 2018; 8(16): 4393-4408.

33. Rocha, S., Targeted drug delivery across the blood brain barrier in Alzheimer's disease.

Curr Pharm Des, 2013; 19(37): 6635-46.

34. Karthivashan, G., et al., Therapeutic strategies and nano-drug delivery applications in

management of ageing Alzheimer's disease. Drug Deliv, 2018; 25(1): 307-320.

35. Abbott, N.J., et al., Structure and function of the blood-brain barrier. Neurobiol Dis.,

2010; 37(1): 13-25.

36. Alavijeh, M.S., et al., Drug metabolism and pharmacokinetics, the blood-brain barrier,

and central nervous system drug discovery. NeuroRx, 2005; 2(4): 554-71.

37. Patra, J.K., et al., Nano based drug delivery systems: recent developments and future

prospects. Journal of Nanobiotechnology, 2018; 16(1): 71.

38. Tiwari, G., et al., Drug delivery systems: An updated review. Int J Pharm Investig, 2012;

2(1): 2-11.

39. Stolp, H.B., et al., Immune responses at brain barriers and implications for brain

development and neurological function in later life. Front Integr Neurosci, 2013; 7: 61.

40. Alkilani, A.Z., M.T. McCrudden, and R.F. Donnelly, Transdermal Drug Delivery:

Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties

of the stratum corneum. Pharmaceutics, 2015; 7(4): 438-70.

41. Vieira, D.B. and L.F. Gamarra, Advances in the use of nanocarriers for cancer diagnosis

and treatment. Einstein (Sao Paulo), 2016; 14(1): 99-103.

42. Kim, J., S.I. Ahn, and Y. Kim, Nanotherapeutics Engineered to Cross the Blood-Brain

Barrier for Advanced Drug Delivery to the Central Nervous System. J Ind Eng Chem.,

2019; 73: 8-18.

43. J., et al., Active Targeting Strategies Using Biological Ligands for Nanoparticle Drug

Delivery Systems. Cancers (Basel), 2019; 11(5).

44. Kinoshita, M., Targeted drug delivery to the brain using focused ultrasound. Top Magn

Reson Imaging, 2006; 17(3): 209-15.



166

45. Upadhyay, R.K., Drug delivery systems, CNS protection, and the blood brain barrier.

Biomed Res Int, 2014; 2014: 869269.

46. Jones, A.R. and E.V. Shusta, Blood-brain barrier transport of therapeutics via receptor-

mediation. Pharm Res., 2007; 24(9): 1759-71.

47. Vieira, D. and L. Gamarra, Multifunctional Nanoparticles for Successful Targeted Drug

Delivery across the Blood-Brain Barrier, 2018.

48. Sheikov, N., et al., Effect of focused ultrasound applied with an ultrasound contrast agent

on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med

Biol, 2008; 34(7): 1093-104.

49. Abbott, N.J., Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell

Mol Neurobiol, 2005; 25(1): 5-23.

50. Abbott, N.J., Astrocyte-endothelial interactions and blood-brain barrier permeability. J

Anat, 2002; 200(6): 629-38.

51. Fernandez-de Retana, S., et al., Intravenous treatment with human recombinant ApoA-I

Milano reduces beta amyloid cerebral deposition in the APP23-transgenic mouse model

of Alzheimer's disease. Neurobiol Aging, 2017; 60: 116-128.

52. Robert, J., et al., Reconstituted high-density lipoproteins acutely reduce soluble brain

Abeta levels in symptomatic APP/PS1 mice. Biochim Biophys Acta, 2016; 1862(5):

1027-36.

53. Retraction for Ajees et al., Crystal structure of human apolipoprotein A-I: Insights into its

protective effect against cardiovascular diseases. Proc Natl Acad Sci U S A, 2018;

115(29): E6966.

54. Wang, F., H.M. Gu, and D.W. Zhang, Caveolin-1 and ATP binding cassette transporter

A1 and G1-mediated cholesterol efflux. Cardiovasc Hematol Disord Drug Targets, 2014;

14(2): 142-8.

55. Rosu, S.A., et al., Amyloidogenic propensity of a natural variant of human apolipoprotein

A-I: stability and interaction with ligands. PLoS One, 2015; 10(5): e0124946.

56. Lewis, T.L., et al., Overexpression of human apolipoprotein A-I preserves cognitive

function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse

model of Alzheimer disease. J Biol Chem, 2010; 285(47): 36958-68.

57. Cukier, A.M.O., et al., Structure-function relationships in reconstituted HDL: Focus on

antioxidative activity and cholesterol efflux capacity. Biochim Biophys Acta Mol Cell

Biol Lipids, 2017; 1862(9): 890-900.



167

58. Rader, D.J., Molecular regulation of HDL metabolism and function: implications for

novel therapies. J Clin Invest, 2006; 116(12): 3090-100.

59. Miller, G.J. and N.E. Miller, Plasma-high-density-lipoprotein concentration and

development of ischaemic heart-disease. Lancet, 1975; 1(7897): 16-9.

60. Brunham, L.R., et al., Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J

Clin Invest, 2006; 116(4): 1052-62.

61. Ji, A., et al., Nascent HDL formation in hepatocytes and role of ABCA1, ABCG1, and SR-

BI. J Lipid Res, 2012; 53(3): 446-55.

62. Rusciano, G., et al., Insights into the interaction of the N-terminal amyloidogenic

polypeptide of ApoA-I with model cellular membranes. Biochim Biophys Acta, 2016;

1860(4): 795-801.

63. Collins, J.C. and L.H. Greene, Biophysical analysis of the transition of an all alpha-

helical Greek-key protein into amyloid fibrils composed of beta-sheet structure. Protein

Pept Lett, 2012; 19(9): 982-90.

64. Campos, E.V.R., et al., Polysaccharides as safer release systems for agrochemicals.

Agronomy for Sustainable Development, 2015; 35(1): 47-66.

65. Pathak, V.M. and Navneet, Review on the current status of polymer degradation: a

microbial approach. Bioresources and Bioprocessing, 2017; 4(1): 15.

66. Sukhanova, A., et al., Dependence of Nanoparticle Toxicity on Their Physical and

Chemical Properties. Nanoscale Research Letters, 2018; 13(1): 44.

67. Fehse, S., et al., Copper transport mediated by nanocarrier systems in a blood-brain

barrier in vitro model. Biomacromolecules, 2014; 15(5): 1910-9.

68. Dube, T., et al., Receptor Targeted Polymeric Nanostructures Capable of Navigating

across the Blood-Brain Barrier for Effective Delivery of Neural Therapeutics. ACS Chem

Neurosci, 2017; 8(10): 2105-2117.

69. Jeevanandam, J., et al., Review on nanoparticles and nanostructured materials: history,

sources, toxicity and regulations. Beilstein J Nanotechnol, 2018; 9: 1050-1074.

70. Patel, A., et al., Recent advances in protein and Peptide drug delivery: a special emphasis

on polymeric nanoparticles. Protein Pept Lett, 2014; 21(11): 1102-20.

71. Marimuthu, M., D. Bennet, and S. Kim, Self-assembled nanoparticles of PLGA-

conjugated glucosamine as a sustained transdermal drug delivery vehicle. Polymer

Journal, 2013; 45(2): 202-209.

72. Makadia, H.K. and S.J. Siegel, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable

Controlled Drug Delivery Carrier. Polymers (Basel), 2011; 3(3): 1377-1397.



168

73. Nabar, G.M., et al., Micelle-templated, poly(lactic-co-glycolic acid) nanoparticles for

hydrophobic drug delivery. Int J Nanomedicine, 2018; 13: 351-366.

74. Zheng, X., et al., Dual-functional nanoparticles for precise drug delivery to Alzheimer's

disease lesions: Targeting mechanisms, pharmacodynamics and safety. Int J Pharm, 2017;

525(1): 237-248.

75. Binda, A., et al., Modulation of the intrinsic neuronal excitability by multifunctional

liposomes tailored for the treatment of Alzheimer's disease. Int J Nanomedicine, 2018; 13:

4059-4071.

76. Hong, S.S., et al., Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances

and Future Perspectives. Pharmaceutics, 2019; 11(10).

77. Arumugam, K., et al., A study of rivastigmine liposomes for delivery into the brain

through intranasal route. Acta Pharm, 2008; 58(3): 287-97.

78. Crowe, T.P., et al., Mechanism of intranasal drug delivery directly to the brain. Life Sci.,

2018; 195: 44-52.

79. Yang, Z.Z., et al., Enhanced brain distribution and pharmacodynamics of rivastigmine by

liposomes following intranasal administration. Int J Pharm, 2013; 452(1-2): 344-54.

80. Kim, J.S., M.S. Kim, and I.H. Baek, Enhanced Bioavailability of Tadalafil after

Intranasal Administration in Beagle Dogs. Pharmaceutics, 2018; 10(4).

81. Wang, H.M., et al., [Intranasal absorption of rivastigmine hydrogen tartrate and brain

targeting evaluation]. Yao Xue Xue Bao, 2016; 51(10): 1616-21.

82. Hadavi, D. and A.A. Poot, Biomaterials for the Treatment of Alzheimer's Disease. Front

Bioeng Biotechnol, 2016; 4: 49.

83. Hu, M.H., et al., A new application of click chemistry in situ: development of fluorescent

probe for specific G-quadruplex topology. Sci Rep, 2015; 5: 17202.

84. Poonthiyil, V., et al., Recent applications of click chemistry for the functionalization of

gold nanoparticles and their conversion to glyco-gold nanoparticles. Beilstein J Org

Chem, 2018; 14: 11-24.

85. Chen, M., et al., Use of curcumin in diagnosis, prevention, and treatment of Alzheimer's

disease. Neural Regen Res., 2018; 13(4): 742-752.

86. Morales, I., et al., The Natural Product Curcumin as a Potential Coadjuvant in

Alzheimer's Treatment. J Alzheimers Dis., 2017; 60(2): 451-460.

87. Azhar Shekoufeh Bahari, L. and H. Hamishehkar, The Impact of Variables on Particle

Size of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers; A Comparative

Literature Review. Adv Pharm Bull, 2016; 6(2): 143-51.



169

88. Das, S., W.K. Ng, and R.B. Tan, Sucrose ester stabilized solid lipid nanoparticles and

nanostructured lipid carriers. II. Evaluation of the imidazole antifungal drug-loaded

nanoparticle dispersions and their gel formulations. Nanotechnology, 2014; 25(10):

105102.

89. Bondi, M.L., et al., Ferulic Acid-Loaded Lipid Nanostructures as Drug Delivery Systems

for Alzheimers Disease: Preparation, Characterization and Cytotoxicity Studies. Current

Nanoscience, 2009; 5(1): 26-32.

90. Montenegro, L., F. Castelli, and M.G. Sarpietro, Differential Scanning Calorimetry

Analyses of Idebenone-Loaded Solid Lipid Nanoparticles Interactions with a Model of

Bio-Membrane: A Comparison with In Vitro Skin Permeation Data. Pharmaceuticals

(Basel), 2018; 11(4).

91. Montenegro, L., et al., Solid Lipid Nanoparticles Loading Idebenone Ester with

Pyroglutamic Acid: In Vitro Antioxidant Activity and In Vivo Topical Efficacy.

Nanomaterials (Basel), 2018; 9(1).

92. Ikeda, K., et al., Inhibition of the formation of amyloid beta-protein fibrils using

biocompatible nanogels as artificial chaperones. FEBS Lett, 2006; 580(28-29): 6587-95.

93. Hull, R.L., et al., Islet Amyloid: A Critical Entity in the Pathogenesis of Type 2 Diabetes.

The Journal of Clinical Endocrinology & Metabolism, 2004; 89(8): 3629-3643.

94. Buskila, Y., A. Bellot-Saez, and J.W. Morley, Generating Brain Waves, the Power of

Astrocytes. Frontiers in Neuroscience, 2019; 13(1125).

95. Martinez-Losa, M., et al., Nav1.1-Overexpressing Interneuron Transplants Restore Brain

Rhythms and Cognition in a Mouse Model of Alzheimer's Disease. Neuron, 2018; 98(1):

75-89.e5.

96. Hanson, J.E., et al., GluN2A NMDA Receptor Enhancement Improves Brain Oscillations,

Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease

Models. Cell Rep, 2020; 30(2): 381-396.e4.

97. Palop, J.J. and L. Mucke, Network abnormalities and interneuron dysfunction in

Alzheimer disease. Nat Rev Neurosci, 2016; 17(12): 777-792.

98. Chackerian, B., Virus-like particle based vaccines for Alzheimer disease. Hum Vaccin,

2010; 6(11): 926-30.

99. Chackerian, B., et al., Virus and virus-like particle-based immunogens for Alzheimer's

disease induce antibody responses against amyloid-beta without concomitant T cell

responses. Vaccine, 2006; 24(37-39): 6321-31.



170

100. Gonzalez-Castro, R., et al., Plant-based chimeric HPV-virus-like particles bearing

amyloid-beta epitopes elicit antibodies able to recognize amyloid plaques in APP-tg

mouse and Alzheimer's disease brains. Inflammopharmacology, 2018; 26(3): 817-827.

101. Ji, M., et al., Hepatitis B core VLP-based mis-disordered tau vaccine elicits strong

immune response and alleviates cognitive deficits and neuropathology progression in

Tau.P301S mouse model of Alzheimer's disease and frontotemporal dementia.

Alzheimers Res Ther, 2018; 10(1): 55.

102. Maphis, N.M., et al., Qss Virus-like particle-based vaccine induces robust immunity

and protects against tauopathy. NPJ Vaccines, 2019; 4: 26.

103. Srinivasarao, M. and P.S. Low, Ligand-Targeted Drug Delivery. Chem Rev, 2017;

117(19): 12133-12164.

104. Din, F.U., et al., Effective use of nanocarriers as drug delivery systems for the treatment

of selected tumors. Int J Nanomedicine, 2017; 12: 7291-7309.

105. Lin, C., et al., Dual-ligand modified liposomes provide effective local targeted delivery

of lung-cancer drug by antibody and tumor lineage-homing cell-penetrating peptide.

Drug Deliv, 2018; 25(1): 256-266.

106. Brohi, R.D., et al., Toxicity of Nanoparticles on the Reproductive System in Animal

Models: A Review. Frontiers in Pharmacology, 2017; 8(606).

107. Smith, et al., - Nanoparticles in Cancer Imaging and Therapy.

Date post:	10-Jul-2020
Category:	Documents
Upload:	others
View:	4 times
Download:	0 times

World Journal of Pharmaceutical Research SJIF Impact Factor 8 - … · 2020-02-29 · Ahmed et al....

Documents